Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
  • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
  • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
  • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
  • C07H19/06—Pyrimidine radicals
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
  • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
  • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
  • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
  • C07H19/16—Purine radicals

Definitions

• This invention relates to antiviral compounds and more particularly to esters, ethers and amides of nucleoside derivatives which are active against human immunodeficiency virus (HIV) , the retrovirus which causes the disease AIDS.
• HIV human immunodeficiency virus
• HIV is fatal, more than 50% of all diagnosed cases having ended in death. HIV and AIDS are today and will remain a worldwide health problem for many years to come.
• Clinical symptoms are weight loss, chronic diarrhoea, persisting fever and opportunistic infections due to loss of T-cells, thus upsetting the overall balance of the immune system. The patient loses his/her ability to combat otherwise insignificant infections.
• European Patent Application No. 0196185A describes pharmaceutical compositions containing AZT, a known compound which has shown great promise in the treatment of AIDS and AIDS- related complex. It is believed that AZT works by inhibiting reverse transcriptase.
• acylation or alkylation of oxygen atoms in the 5'-position or in the purine or pyrimidine ring and/or acylation or alkylation of - 2a - exocylic or endocyclic nitrogen atoms present in the purine or pyrimidine ring can give significant advantages in terms of uptake, overall activity and site of action.
• Our PCT Application O88/07532 describes certain esters and amides of this type carrying acyl groups at the 5' position or on exocyclic nitrogens; the present invention extends this principle to a wider range of related compounds.
• A is a fluorine atom and B is a hydrogen atom or A and B together represents a carbon-carbon bond
• Y is a hydrogen atom or a physiologically acceptable group of the formula
• n O or 1
• m 0 or 1
• R 1 is an optionally substituted alkyl or aryl group or an N-(C _ alkyl)-1,4-dihydropyridin- 3-yl group or, where n is 0, a hydrogen atom;
• R 2 and R3 are independently hydrogen atoms or lower alkyl groups; and
• X is a group selected from
• R4 i.s a hydrogen atom or a group
• Y3 and Y4 have the above meanings and R5 is a hydrogen or halogen atom or a lower alkyl or trifluoro ethyi group, with the proviso that at least one of the groups Y 1, Y2, Y3 and Y4 is other than hydrogen, and that when all of those groups Y 2, Y3 and
• Y 4 whi•ch are present are hydrogen, then Y1 is a group
• compositions for the treatment or prophylaxis of retrovirus infections in particular neurotropic viruses and especially HIV infections.
• Such compositions also form part of the invention.
• the group R is preferably an alkyl group - 5 - containing 1-20 carbon atoms which may be straight or branched, or an aryl group which may contain 6 to 20 carbon atoms and may be mono- or poly-cyclic.
• Substituents which may be present on the alkyl groups R include aryl groups preferably having 6-10 carbon atoms (as in aralkyl groupings) , alkoxy, hydroxy, acyloxy, amino, acylamino and carboxy groups.
• the acyl groups in the acyloxy and acylamino groups may be lower alkanoyl groups, e.g. C 1 . 6 alkanoyl groups.
• Aryl groups include 5- or 6-membered heterocyclic aryl groups having one or more heteroatoms selected from O, N and S, such as furyl, imidazolyl, pyrrolyl, pyridinyl and thienyl groups.
• Substituents which may be present on aryl groups include alkyl groups, e.g. having 1-6 carbon atoms, hydroxy and carboxy groups. Examples of such groups include methyl, ethyl, propyl, t-butyl, pentyl, stearyl, palmityl, carboxyethyl and benzyl groups.
• the lower alkyl groups R 2, R3 and R5 preferably contain 1-6 carbon atoms. However, R 2 preferably represents a hydrogen atom.
• R 3 i.s preferably a hydrogen atom or more preferably a methyl group.
• R is a halogen atom it may be a fluorine, chlorine, bromine or iodine atom.
• R 5 is preferably a hydrogen or chlorine atom or a methyl group.
• R in any of the groups Y , Y , Y or Y is an N-alkyl-l,4-dihydropyridin-3-yl group the alkyl group is preferably methyl.
• the compounds of the invention may carry more than one of the groups Y 1, Y2, Y 3 and Y4.
• the compounds of formula (I) D,E, I and
• Groups Y 2 are preferably of the formula R1.CO-,
• the salts of the compounds of formula (I) may be acid addition salts with organic or inorganic acids, for instance hydrochloric or phosphoric acid or methanesulphonic acid, ethane disulphonic acid,
• Antiviral counter-ions such as phosphonoformate or suramin may also be used.
• Organic or inorganic base salts may be formed with acidic groups present in the molecule; suitable counter-ions include alkali metal ions such as sodium and potassium ions, divalent ions such as calcium and zinc ions and organic ions such as tetraalkylammoniu and choline or ions derived from meglumine or ethylenediamine. Salts according to the invention may be formed by reaction of the compound of formula (I) with an appropriate acid or base.
• compositions according to the invention may be used in the treatment and/or prophylaxis of retrovirus infections, in particular HIV infections, and such a method forms a further feature of the invention. They may be formulated in conventional manner by admixture of one or more compounds of formula (I) as defined above with excipients and/or carriers.
• the compounds of formula (I) may themselves be inhibitors of reverse transcriptase when the 5'- hydroxy group is free it is also possible that they are converted .in vivo to the 5'-hydroxy-2' ,3'-dideoxy- 3'-fluoronucleosides or 5'-hydroxy-2' ,3'-dideoxy-2' ,3 '- didehydro nucleosides. Nevertheless the substitution at the respective O- and N- atoms gives surprising advantages in terms of uptake and sustained activity.
• the compounds of formula (I) are more lipophilic than the parent compounds and this permits rapid and efficient absorption from the gastro-intestinal tract; the absorption rate may be optimised by careful choice of the substituent group to give the desired balance of lipophilicity and hydrophilicity.
• the lipophilic nature of the compounds of formula (I) also gives the molecules the ability to penetrate the cell membranes more easily and leads to higher intracellular concentrations, giving an improved dose/effect ratio.
• the steady hydrolysis of the compounds ensures a sustained concentration of the active compound in the cell and thereby permits longer - 7 - intervals between doses, overcoming a significant drawback of the prior art compounds.
• the compounds according to the invention can penetrate the blood-brain barrier and thus permit treatment of the neurological disorders which have been observed to be related to the presence of neurotropic viruses, e.g. retroviruses such as HIV, and lentiviruses (Yarchoan et al, The Lancet, January 17, 1987, page 132).
• neurotropic viruses e.g. retroviruses such as HIV, and lentiviruses
• This is a significant advantage compared to the corresponding unsubstituted compounds or other antiviral compounds and is not referred to anywhere in the prior art. Attempts have been made to treat these neurological disorders with AZT but with limited success.
• the invention thus further provides a method of treatment of neurological disorders caused by neurotropic viruses wherein an effective dose of a compound of formula (I) or a salt thereof is administered to a patient suffering from such a disorder.
• A, B and Y 1 are as hereinbefore defined and XB is as hereinbefore defined for X except that any of the groups Y 1, Y2, Y3 and Y4 may each addi.tionally represent a protecting group, with the proviso that at least one of Y 1, Y2, Y3 and Y4 i.s a hydrogen atom] with a reagent serving to introduce a group R 1(0) CO. (OCR2R3) as defined above followed where required by removal of any protecting groups and/or unwanted substituents so introduced.
• OCR2R3 group R 1(0) CO.
• Y 3 and Y4 remain as hydrogen atoms, it may be desirable to protect the latter first, to form a compound of formula (I) in which one or more of Y 1, Y2, Y3 and Y4 are protecting groups, these being removed after introduction of the desired acyl or ether group.
• protecting groups may, in fact, be conventional N- or
• O-protecting groups including groups R OCO- which may be selectively removed in the presence of the group(s) intended to remain.
• N-benzyloxycarbonyl may be used to protect an exocylic amino group and if the group which is intended to remain is not one which is removable by reduction, for example a straight chain alkoxycarbonyl group, the
• N-benzyloxycarbonyl group can readily be removed selectively using hydrogen and a noble metal catalyst such as palladium.
• Trisubstituted silyl groups may also be used as protecting groups, especially for the
• 5'-oxygen atom examples include trialkylsilyl e.g. trimethylsilyl, dimethyl- t-butylsilyl, and thexyldimethyl silyl groups.
• trialkylsilyl e.g. trimethylsilyl, dimethyl- t-butylsilyl, and thexyldimethyl silyl groups.
• Y 4 are hydrogen, and a mixture of compounds is produced, the individual components may readily be separated, for example by chromatography.
• 5'-O-monoalkylation is to be effected (i.e. introduction of a group Y in which m is 1) it is especially effective to form a dianion of the nucleoside (e.g. by reacting with sodium hydride) and to react this with one equivalent of the alkylating agent. It is of course, still possible to use protected forms of the nucleoside, for example by acylation of a nucleophilic nitrogen atom before salt formation with sodium hydride. - 9 -
• Suitable acylating agents for use in the reaction have the formula Ac-L where L is a leaving group.
• suitable acylating agents include the acid halides and acid anhydrides advantageously in the presence of a base;
• acylating agents include the haloformate esters and reactive carbonic acid diesters.
• the halogen may, for example, be chlorine or bromine.
• the base for use in the reaction with the acid halide or anhydride may, for example, be a heterocyclic base such as pyridine or
• 4-dimethylaminopyridine increases the speed of the reaction and may be used advantageously with pyridine.
• the reaction will normally be carried out in the presence of an inert solvent e.g. a substituted amide solvent such as dimethylformamide, dimethyl- acetamide or a halogenated hydrocarbon such as dichloromethane.
• an inert solvent e.g. a substituted amide solvent such as dimethylformamide, dimethyl- acetamide or a halogenated hydrocarbon such as dichloromethane.
• N-acylation or even N-diacylation predominates.
• N-acyl groups R CO- may be removed selectively, for example by reaction with a phenol such as p-methyl-pheno1. Where multiple substitution is to be effected, a stronger base such as sodium hydride may be advantageous.
• R 1 .O.CO.NH- on the base This may conveniently be used in the preparation of N-acyl compounds by blocking the
• Suitable acyloxyalkylating agents for use in the invention will in general be of the formula
• R 1CO.O.CR2R3L or R1O.CO.O.CR2R3L where L is a leaving group.
• the group L may for example, be a halogen atom such as a chlorine or bromine atom or a hydrocarbon-sulphonyloxy group such as a tosyloxy or mesyloxy group.
• the alkylation reaction will normally be effected in the presence of a base, conveniently an inorganic carbonate such as potassium carbonate or an alkali metal hydride such as sodium hydride.
• a base conveniently an inorganic carbonate such as potassium carbonate or an alkali metal hydride such as sodium hydride.
• Bases as used for acylation may also be useful.
• Y 2, Y3 and Y4 are all hydrogen atoms are well described in the literature (see for example the literature references cited in the introduction hereto) .
• Starting compounds wherein one or more of Y 1, Y2, Y3 and Y4 are other than hydrogen may be prepared by preliminary reactions as described above.
• compositions according to the invention may be formulated conventionally by means well known in the art, and may be administered by any convenient route, for instance orally, rectally, vaginally, intraveneously or intramuscularly.
• suitable formulations include tablets and capsules, aqueous formulations for intravenous injection and oil-based formulations for intramuscular injection. Suitable dosages will lie in the range 0.1 to lOOmg per kilogram of bodyweight per 24 hour period.
• the compositions according to the invention may also contain other active antivirals for instance acyclovir, phosphonofor ate, suramin, Evans Blue, interferons or AZT.
• 3 '-Fluoro-2 • ,3 '-dideoxycytidine (0.2 mmol) is dissolved in a mixture of pyridine (0.5 ml) and DMF (0.5 ml), the solution cooled to 0°C, benzyl chlorofor ate (0.5 mmol) and 4-N,N-dimethylamino- pyridine (0.2 mmol) added, the mixture stirred at ambient temperature for 12 hours, water (4 ml) added, the mixture evaporated at reduced pressure, and the residue chromatographed on silica gel. The title compound is eluted with chloroform:ethanol (99:1) .
• N 4 -Benzyloxycarbonyl-3 '-fluoro-5'-O-pivaloyloxymethyl- 2',3 '-dideoxycytidine (0.1 mmol) is added to a suspension of 5% palladium on charcoal (8 mg) in ethanol (4 ml) .
• the hydrogenolysis is run at atmospheric pressure using a Brown apparatus where the hydrogen gas is generated in a controlled manner by the addition of 3 N HCl to a solution of sodium hydride in a separate compartment.
• the reaction is run at ambient temperature and is monitored by TLC in order to ensure that over- reduction in the heterocyclic ring does not occur.
• the reaction time is normally about 1 hour.
• the mixture is then filtered through a thin bed of Celite, the filtrate evaporated and the product purified by chromatography on silica gel using chloroform:ethanol (9:1).
• Thexyldimethylsilyl chloride (0.25 mmol) is added, and the reaction mixture is stirred at ambient temperature for 24 hours.
• the solvent is removed at reduced pressure, chloroform (15 ml) added to the residue, washed with water (5 ml x 2) , and the dried (MgSO.) solution evaporated.
• the residue is chromatographed on silica gel using ethyl acetate-hexane to furnish 3 '-Fluoro-5'- O-thexyldimethylsilyl-3 '-deoxythymidine.
• the silyl group is removed by dissolution of the product (1 mmol) in THF (1 ml) and adding 0.25 M solution of tetrabutylammonium fluoride in THF (1 ml) .
• the mixture is stirred at ambient temperature for 20 minutes, the solvent evaporated, the residue dissolved in chloroform (10 ml) , washed with water (2 ml) , dried (MgSO ) , evaporated, and the residue purified by preparative chromatography on silica gel using chloroform-methanol.
• 1-(2,3-Dideoxy- ⁇ -D-glycero-pent-2-enofuranosyl)uracil (0.2 mmol) and 4-N,N-dimethylaminopyridine (0.25 mmol) are dissolved in pyridine (3 ml) , the solution cooled to 0"C, propionic anhydride (0.3 mmol) added, the mixture stirred at ambient temperature for 24 hours, the solvent evaporated at reduced pressure, toluene added, the mixture reevaporated at reduced pressure, and the residue chromatographed on silica using chloroform and subsequently chloroform- methanol.
• the product thus obtained is 1-f5-Q- propionyl-2.3-dideo ⁇ y- ⁇ -D-qlycero-pent-2-enofuranosyl) uracil.
• 1-(2,3-Dideoxy- ⁇ -D-glycero-pent-2-enofuranosyl)cytosine (0.1 mmol) is dissolved in a mixture of pyridine (0.5 ml) and DMF (0.5 ml), the solution cooled to 0°C, ethyl chloroformate (0.3 mmol) and 4-
• the silyl group is removed by dissolution of the product (1 mmol) in THF (1 ml) and adding 0.25 M solution of tetrabutylammonium fluoride in THF (1 ml) .
• the mixture is stirred at ambient temperature for 15 minutes, the solvent evaporated, the residue dissolved in chloroform (10 ml) , washed with water (2 ml) , dried (MgSO.) , evaporated, and the residue purified by preparative chromatography on silica gel using chloroform-methanol.
• the suspension was stirred vigorously under nitrogen at ambient temperature for 1 hour, cooled to 0°C and chloroethyl ethyl carbonate (0.100 ml, 0.748 mmol) added, the mixture stirred at 40°C overnight, additional chloroethyl ethyl carbonate (0.05 ml, 0.374 mmol) added and the mixture stirred at 40°C for another 3 hours.
• the solvent was then removed at reduced pressure, the residue extracted into hexane: ethyl acetate (2:1) and chromatographed on the "chromatotron"; yield 0.143 g (54 %) of a colourless oil.
• N 6 -Ethyloxycarbonyl-9-(2,3-dideoxy-g-D-qlvcero-pent- 2-enofuranosyl)adenine A solution of anhydrous tetrabutylammonium fluoride (48 mg) in dry THF (1 ml) was added dropwise with stirring to a solution of N 6 -ethyloxycarbonyl-9-(5-0-thexyldimethylsilyl-2,3- dideoxy-0-D-glycero-pent-2-enofuranosyl)adenine (10 mg) in THF (1 ml) under nitrogen at 0"C.
• N 6 -Ethyloxycarbonyl-9-(5-0- ⁇ -acetoxyisobutyryl-2,3- dideoxy-g-D-qlycero-pent-2-enofuranosyl)adenine N- Methyl imidazole (7 mmol) and ethyl chloroformate (7 mmol) were added to a solution of 9-(5-0- ⁇ - acetoxyisobutyryl-2,3-dideoxy-?-D-glycero-pent-2- enofuranosyl)adenine (250 mg, 0.69 mmol), the mixture stirred at ambient temperature for 12 hours, the solvent evaporated and the product purified by flash chromatography on silica gel using chloroform:methanol (50:1); yield 135 mg (45 %) .
• N 6 -Ethyloxycarbonyl-9-(2,3-dideoxy- ⁇ -D-qlvcero-pent- 2-enofuranosyl)adenine was added to a solution of N 6 - ethyloxycarbonyl-9-(5-0- ⁇ -acetoxyisobutyryl-2,3-dideoxy- /3-D-glycero-pent-2-enofuranosyl)adenine (20 mg) in dry DMF (0.5 ml) with stirring, the mixture stirred at ambient temperature for 3 min before a stream of dry ammonia was passed through the mixture for 15 min. Water (10 ml) was then added, the mixture freeze-dried and the residue subjected to flash chromatorgraphy on silica gel using chloroform:methanol (10:1); yield 16 mg.
• Tetrabutylammonium fluoride in THF (0.25 M; 1.60 ml, 0.40 mmol) wa ⁇ added to a ⁇ olution of 1- pivaloyloxymethyl-9-(5-0-thexyldimethyl ⁇ ilyl-2,3- dideoxy-?-D-glycero-pent-2-enofurano ⁇ yl)hypoxanthine (34 mg, 0.073 mmol) in dry THF (3 ml) with stirring under nitrogen at 0°C, the mixture stirred at ambient temperature for 40 min, the solvent removed by evaporation and the residual material ⁇ ubjected to fla ⁇ h chromatography on silica gel using chloroform:ethanol (9:1); yield 20 mg (78 %) of an oily material.
• Chloromethyl propionate was prepared by the method described by Benneche et al. (Acta Chem. Scand. , 4_3, (1988), 74). Bp. 53°C/3 mm Hg
• Thexyldimethylsilyl chloride (7.00 ml, 35.69 mmol) was - 45 - added to a solution of N 4 -ethyloxycarbonylcytidine (9.39 g, 29.80 mmol) and imidazole (4.45 g, 65.35 mmol) in DMF (120 ml) under nitrogen at ambient temperature, the mixture stirred at ambient temperature for 26 hours before the solvent was removed by distillation at reduced pressure. The residue was dissolved in a mixture of chloroform:diethyl ether:ethanol (5:4:1; 50 ml) and subjected to flash chromatography on silica gel; yield 10.89 g (80 %) .
• the reaction was worked up by the addition of diethyl ether (50 ml) , the solution washed with water (2 x 5 ml) , dried (MgS0 4 ) and the solvents distilled off.
• the residual material was subjected to flash chromatography on silica gel using chloroform:ethyl acetate (9:1) and thereafter chromatography on the "chromatotron" using chloroform:diethyl ether:ethanol (5:4:1); yield 0.51 g - 46 - chloroform:diethyl ether:ethanol (5:4:1); yield 0.51 g (34 %).
• N-Ethyloxycarbonyl-3-pivaloyloxymethyl-l-(2,3-dideoxy-ff- D-glycero-pent-2-enofuranosyl)cytosine was the first product eluted; yield 0.009 g (13 %) .
• N 4 -Ethyloxycarbonyl-N 4 -pivaloyloxymethyl-l-(2,3-dideoxy- /3-D-glycero-pent-2-enofuranosyl)cytosine wa ⁇ the second product eluted; yield 0.009 g, (13 %) .
• the organic phase was separated, dried (MgS0 4 ) and evaporated.
• the residual material was a mixture of the desired product and 1-(2,3-dideoxy-3-D-glycero-pent-2-enofuranosyl)-3- - 49 - pivaloyloxymethyluracil which were separated by chromatography on silica gel.
• the desired product was eluted using hexane:ethyl acetate (1:1).
• 3'-Fluoro-2'3'-dideoxyuridine (50.5 mg, 0.219 mmol, prepared as described by Herdewijn et al. (Nucleoside ⁇ & Nucleotides, 8, (1989), 65) was dissolved in pyridine (2 ml), 4-dimethylaminopyridine (30 mg, 0.246 mmol) added and the solution cooled to 0°C. Diethyl pyrocarbonate (0.150 ml, 1.04 mmol) was added and the mixture stirred at ambient temperature for 12 hours, the solvent evaporated under reduced pressure, toluene added and the mixture reevaporated. Addition of toluene and reevaporation was repeated once and the residue chromatographed on silica gel using chloroform - methanol (95:5) ; yield 62 mg (94 %) of title compound as a foam.
• White soft paraffin is melted and incorporated into the liquid paraffin and stirred until the mixture is cold.
• Active compound is triturated with a portion of the basis and gradually the remainder of the basis was incorporated.
• the ointment is filled into lacquered aluminium tubes (20 g) and sealed. The ointment contains 0.1 % active compound. - 52 -
• Polysorbate 80, Sorbitol and benzyl alcohol are dis ⁇ olved in 500 ml di ⁇ tilled water. Active compound is screened through a 0.15 mm sieve and dispersed in the solution under vigorous stirring. The pH is adjusted to 4.5 by dropwise addition of 1M HCl. Water is added to 1000 ml, the suspension was filled in 1 ml vials The vials are sterilized by a -radiation. Each vial contains 200 mg active compound.
• Active compound and lactose are screened through a 0.15 mm sieve and mixed together for 10 minutes.
• the mixed powder is wetted with an aqueous solution of polyvinyl-pyrrolidone.
• the mass is granulated, and the dried (40 °C) granulate is mixed with starch, talcum powder and magnesium stearate.
• the granulate is compressed into tablets.
• the tablet diameter is 11 mm
• the tablet weight is 350 mg and each tablet contains 200 mg active compound.
• Methyl p-hydroxybenzoate (70 mg) and propyl p-hydroxy- benzoate (15 mg) are dissolved in water (100 ml) at 90 °C. After cooling to 30 °C methyl cellulose (2g) is added and the mixture is agitated for 3 hours. 1 gram active compound are screened through a 0.15 mm sieve, and dispersed in the solution under vigorous stirring. The ⁇ u ⁇ pen ⁇ ion i ⁇ filled in a 100 ml tube. The suspension contain 10 mg active compound/ml.
• Carboxymethyl cellulose, sorbitol and sodium benzoate are dissolved in water with stirring for 2 hours. A solution of the essence ⁇ in ethanol is added. Active compound is screened through a 0.15 mm sieve and dispersed in the solution under vigorous stirring. The suspension (10 gram) is filled in a 20 ml tube. Each tube contains 200 mg active compound.
• Active compound hydroxypropyl-methylcellulose and lactose are mixed together for 20 minutes and granulated with a solution of povidone. Magnesium stearate is added and the mixture is compressed into tablets.
• the tablet diameter is 13 mm, the tablet weight is 700 mg and each tablet contains 500 mg active compound.

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• 1990
  • 1990-11-06 CA CA002073063A patent/CA2073063A1/en not_active Abandoned
  • 1990-11-06 WO PCT/EP1990/001853 patent/WO1991006554A1/en not_active Application Discontinuation
  • 1990-11-06 JP JP2514754A patent/JPH05501404A/ja active Pending
  • 1990-11-06 EP EP90916194A patent/EP0500610A1/de not_active Withdrawn
  • 1990-11-06 AU AU66192/90A patent/AU636678B2/en not_active Ceased
• 1992
  • 1992-05-05 FI FI922014A patent/FI922014A/fi not_active Application Discontinuation
  • 1992-05-05 OA OA60203A patent/OA09697A/en unknown

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